Production of oxetanones

Abstract

The invention relates to a novel process for producing a compound having the formula ##STR1## wherein R 1 , R 2 and X are described herein, via wherein R corresponding β-keto- and β-hydroxy-δ-lactones, as well as novel intermediates which occur in the process.

We claim: 
     
       1. A process for producing a compound having the formula ##STR15## wherein R 1  and R 2  each are independently alkyl with up to 17 C atoms optionally interrupted by an O atom in a position other than the α- or β-position; or benzyl optionally ring-substituted by 1 or 3 C 1-6  -alkyl or C 1-6  -alkoxy groups, X is hydrogen or a group of the formula (R 3 , R 4 )NCH(R 5 )(CH 2 ) n  --CO--,   R 3  is hydrogen, C 1-3  -alkyl or C 1-3  -alkanoyl,   R 4  is hydrogen or C 1-3  -alkyl and   R 5  is hydrogen, a group Ar or Ar-C 1-3  -alkyl or C 1-7  -alkyl optionally interrupted by Y and optionally substituted by Z or   R 4  with R 5  form together with the N atom to which they are attached to a 4- or 6-membered saturated ring,   Y is oxygen, sulphur or a group N(R 6 ) C(O)N(R 6 ) or N(R 6 )C(O),   Z is a group --(O or S)--R 7 , --N(R 7 , R 8 ), --C(O)N(R 7 , R 8 ) or --N(R 7 )C(O))R 8 ,   n is the number 1 or 0, whereby R 5  is hydrogen when n is the number 1,   Ar is phenyl substituted by 1 to 3 groups R 9  or OR 9  and   R 6  to R 9  are hydrogen or C 1-3  -alkyl, and of salts of the compounds of formula I in which X is not hydrogen with weak acids, which process comprises the steps of:   a) etherifying a β-hydroxy-δ-lactone of the formula ##STR16## b) opening the resulting ether of the formula ##STR17##  wherein T is a readily cleavable ether group, with a base, c) reacting the resulting salt of the formula   R.sup.2 --CHOHCH.sub.2 --CH(O--T)CH(R.sup.1)COO--M         IV        wherein M is an alkali metal or alkaline earth metal, in optional sequence with an arylmethyl halide and a base and   d) selectively cleaving the resulting diether of the formula   R.sup.2 --CH(OCH.sub.2 --Ar)CH.sub.2 CH(O--T)CH(R.sup.1)COO--M V        with an acid,   e) cyclizing the resulting β-hydroxyacid of the formula   R.sup.2 --CH(OCH.sub.2 --Ar)CH.sub.2 CHOHCH(R.sup.1)COOH   VI        optionally after resolution into its enantiomers, and   f) cleaving the resulting β-lactone ether of the formula ##STR18##  to form the compound of formula I, wherein X is hydrogen, and g) where a compound of formula I is required, wherein X is not hydrogen, esterifying the resulting β-lactone alcohol of formula I in which X is hydrogen with an agent which introduces the group X, and   h) where a salt of a compound of formula I, wherein X is not hydrogen, is required, isolating the ester obtained in the form of a salt with a weak acid.     
     
     
       2. A process according to claim 1, wherein an alkali metal hydride is used as the base in step c). 
     
     
       3. A process according to claim 1 for producing a compound having the formula ##STR19## wherein wherein R 1  and R 2  each ar e independently alkyl up to 17 C atoms optionally interrupted by an O atom n a position other than and α- or β-position; or benzyl optionally ring-substituted by 1 to 3 C 1-6  -alkyl or C 1-6  -alkoxy groups, X' is a group of the formula (R 3 , R 4 )NCH(R 5 )(CH 2 ) n  --CO--,   R 3  is hydrogen, C 1-3  -alkyl or C 1-3  -alkanoyl,   R 4  is hydrogen or C 1-3  -alkyl and   R 5  is hydrogen, a group Ar or Ar-C 1-3  -alkyl or C 1-7  -alkyl optionally interrupted by Y and optionally substituted by Z or   R 4  with R 5  form together with the N atom to which they are attached to a 4- or 6-membered saturated ring,   Y is oxygen, sulphur or a group N(R 6 ), C(O)N(R 6 ) or N(R 6 )C(O),   Z is a group --(O or S)--R 7 , --N(R 7 , R 8 ), --C(O)N(R 7 , R 8 ) or --N(R 7 )C(O))R 8 ,   n is the number 1 or 0, whereby R 5  is hydrogen when n is the number 1,   Ar is phenyl substituted by 1 to 3 groups R 9  or OR 9  and   R 6  to R 9  are hydrogen or C 1-3  -alkyl, and of salts of the compounds of formula I in which X is not hydrogen with weak acids, which process comprises the steps of:   a) reacting a compound of the formula   CH.sub.3 COCH(R.sup.1)COO--R                               XIII        where R is C 1-4  -alkyl with a compound of the formula   R.sup.2 --CHO                                              XVII     to form a compound having the formula     R.sup.2 --CHOHCH.sub.2 COCH(R.sup.1)COO--R                 XI,       b) cyclizing the compound of formula XI to form a compound of the formula ##STR20## c) catalytically hydrogenating the compound of formula XII to form a compound of the formula ##STR21## d) etherifying the compound of formula II, e) opening the resulting ether of the formula ##STR22##  wherein T is a readily cleavable ether group, with a base, f) reacting the resulting salt of the formula   R.sup.2 --CHOHCH.sub.2 --CH(O--T)CH(R.sup.1)COO--M         IV     wherein M is an alkali metal of alkaline earth metal, in optional sequence with an arylmethyl halide and a base     g) selectively cleaving the resulting ether of the formula ti R 2  --CH(OCH--Ar)CH 2  CH(O--T)CH(R 1 )COO--M tm V      with an acid,   h) cyclizing the resulting β-hydroxyacid of the formula   R.sup.2 --CH(OCH--Ar)CH.sub.2 CHOHCH(R.sup.1)COOH          VI        optionally after resolution into its enantiomers,   i) cleaving the resulting β-lactone ether of the formula ##STR23##  to give the compound of formula I, wherein X is hydrogen, and j) esterifying the resulting compound of formula I wherein X is hydrogen with an agent which introduces the group X', to give the compound of formula I'.     
     
     
       4. A process according to claim 3, wherein R 1  was n-hexyl and R 2  was undecyl. 
     
     
       5. A process for producing a compound having the formula: ##STR24## wherein R 1  and R 2  each, independently, is alkyl with up to 17 C atoms optionally interrupted by an O atom in a position other than the α- or β-position, or benzyl optionally ring-substituted by 1 to 3 C 1-6  -alkyl or C 1-6  -alkoxy groups; Ar is phenyl substituted by 1 to 3 R 9  or OR 9  groups wherein R 9  is hydrogen or C 1-3  -alkyl; which process comprises the steps of: (a) reacting a compound of the formula:   R.sup.2 --CHOHCH.sub.2 CHO(O--T)CH(R.sup.1)COO--M          IV        wherein T is a readily cleavable ether group and M is an alkali metal or alkaline earth metal, in optional sequence with an arylmethyl halide and a base; and   (b) selectively cleaving the resulting diether of the formula:   R.sup.2 --CH(OCH.sub.2 -Ar)CH.sub.2 CH(O--T)CH(R.sup.1)COO--M V        with an acid,   (c) cyclizing the resulting β-hydroxyacid of the formula:   R.sup.2 --CH(OCH.sub.2 --Ar)CH.sub.2 CHOHCH(R.sup.1)COOH   VI        optionally after resolution into its enantiomers, to form the compound of formula VII.   
     
     
       6. A process according to claim 5 wherein R 1  is n-hexyl and R 2  is undecyl. 
     
     
       7. A process according to claim 6 for producing (3S,4S)-3-hexyl-4-[(R)-2-benzyloxytridecyl ]-2-hexyl-2-oxetanone which comprises the steps of: (a) reacting the sodium salt of (2RS,3RS,5SR)-2-hexyl-5-hydroxy-3-(tetrahydro-2H-pyran-2-yloxy) hexadecanoic acid with benzyl bromide and sodium hydride in THF;   (b) selectively cleaving the resulting sodium salt of (2RS,3RS,5SR)-2-hexyl-5-benzyloxy-3-(tetrahydro-2H-pyran-2-yloxy) hexadecanoic acid with hydrochloric acid;   (c) resolving into its enantiomers, the resulting rac-(2RS,3RS, 5SR)-5-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid; and   (d) cyclizing the isolated (2S,3S,5R)-5-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid with benzenesulphonyl chloride to form (3S,4S)-4-[(R)-2-benzyloxytridecyl]-3-hexyl-2-oxetanone.   
     
     
       8. A process according to claim 1, wherein the compound of the formula   R.sup.2 --CH(OCH.sub.2 --Ar)CH.sub.2 CHOHCH(R.sup.1)COOH   VI     is resolved into its enantiomers prior to being cyclized.   
     
     
       9. A process according to claim 8, wherein the compound of the formula ##STR25## is cleaved by hydrogenation to form a compound of formula I wherein X is hydrogen, the resulting compound of formula I is purified and isolated by crystallization.